Cutaneous T-cell lymphoma (CTCL) is a chronic incurable disease with significant morbidity and mortality. Treatment of CTCL depends on clinical stage and includes both topical and systemic therapies, including psoralene plus UVA irradiation (PUVA), total skin electron beam therapy (TSEBT), systemic chemotherapy, and 3 newly approved drugs (vorinostat, romidepsin, and pralatrexate), which have been FDA- approved based on overall response rates of 29% to 34%. These interventions are associated with sometimes debilitating and dose-limiting side effects and are not curative.1,32 Partial responses, progression and relapses do often occur, and prolonged disease-free survival is rare except in patients with early stage CTCL.32 CTCL is highly responsive to radiotherapy, and TSEBT has evolved as a powerful treatment regimen. Current low-dose (8-10 Gy) TSEBT treatment regimens can generate very good responses with minimal toxicity. However, relapses occur, and doses are gradually increased. High-dose (30-36 Gy) treatment regimens of are commonly used resulting in complete response (CR) rates ranging from 98% in limited plaque stage to 36% in tumor stage. The CR rate is correlated with total radiation dose, but most patients will eventually relapse. However, high-dose TSEBT is generally not repeated more than twice due to the concern of causing significant toxicity such as skin atrophy and necrosis.29-33 In phase I and phase II clinical studies, interleukin-12 (IL-12) monotherapy was shown to be effective in CTCL, inducing tumor regression and achieving some complete responses.4,12,13 Recombinant human interleukin-12 (rHuIL-12) has also been shown to be effective as a mitigator of radiation-induced hematopoietic and skin toxicity (Figures 1, 7-10).17 With rHuIL-12, we propose to induce significant antitumor clinical responses in synergy with the radiation therapy, while providing radiation protection to normal tissues. rHuIL- 12 is an optimal adjuvant for radiation therapy in CTCL for several reasons: 1) rHuIL-12 effectively mitigates radiation side effects (Figures 1, 7-10); 2) rHuIL-12 exhibits independent antitumor activity in CTCL (Fig. 2- 6)11-13; and 3) together with radiation-induced immunogenic tumor cell death,10 rHuIL-12 modulates tumor microenvironment to potentiate tumor antigen uptake and presentation by APCs, blocks activity of cells capable of immune suppression14,15, resulting in a Th1-skewing and antitumor-stimulating immune environment15, leading to long-lasting antitumor immunity likely via an endogenous vaccine effect (Fig. 3).16,33 The proposed project is a phase I clinical study of rHuIL-12 in combination with TSEBT in patients with CTCL. The specific aims or objectives of the project are: 1) Determine the safety of rHuIL- 12 in patients with CTCL treated with low-dose TSEBT; 2) Establish a recommended phase II dose (RP2D) of rHuIL-12; and 3) Explore efficacy endpoints of rHuIL-12 in patients with CTCL treated with low-dose TSEBT.